TY - JOUR
T1 - Total body irradiation causes residual bone marrow injury by induction of persistent oxidative stress in murine hematopoietic stem cells
AU - Wang, Yong
AU - Liu, Lingbo
AU - Pazhanisamy, Senthil K.
AU - Li, Hongliang
AU - Meng, Aimin
AU - Zhou, Daohong
N1 - Funding Information:
The authors thank Mrs. Aimin Yang for her excellent technical assistance. This study was supported in part by grants from the National Institutes of Health (R01-CA078688, R01-CA086688, and CA102558 to Dr. Daohong Zhou and P30 CA138313 to the Hollings Cancer Center and the Flow Cytometry & Cell Sorting Shared Resource) and a grant from the National Natural Science Foundation of China (NSFC 30828011 to Dr. Daohong Zhou). This work was also supported by the National Institutes of Health, Grant C06 RR014516 from the Extramural Research Facilities Program of the National Center for Research Resources.
PY - 2010/1/15
Y1 - 2010/1/15
N2 - Ionizing radiation (IR) and/or chemotherapy causes not only acute tissue damage but also late effects including long-term (or residual) bone marrow (BM) injury. The induction of residual BM injury is primarily attributable to the induction of hematopoietic stem cell (HSC) senescence. However, the molecular mechanisms by which IR and/or chemotherapy induces HSC senescence have not been clearly defined, nor has an effective treatment been developed to ameliorate the injury. Thus, we investigated these mechanisms in this study. The results from this study show that exposure of mice to a sublethal dose of total body irradiation (TBI) induced a persistent increase in reactive oxygen species (ROS) production in HSCs only. The induction of chronic oxidative stress in HSCs was associated with sustained increases in oxidative DNA damage, DNA double-strand breaks (DSBs), inhibition of HSC clonogenic function, and induction of HSC senescence but not apoptosis. Treatment of the irradiated mice with N-acetylcysteine after TBI significantly attenuated IR-induced inhibition of HSC clonogenic function and reduction of HSC long-term engraftment after transplantation. The induction of chronic oxidative stress in HSCs by TBI is probably attributable to the up-regulation of NADPH oxidase 4 (NOX4), because irradiated HSCs expressed an increased level of NOX4, and inhibition of NOX activity with diphenylene iodonium but not apocynin significantly reduced TBI-induced increases in ROS production, oxidative DNA damage, and DNA DSBs in HSCs and dramatically improved HSC clonogenic function. These findings provide the foremost direct evidence demonstrating that TBI selectively induces chronic oxidative stress in HSCs at least in part via up-regulation of NOX4, which leads to the induction of HSC senescence and residual BM injury.
AB - Ionizing radiation (IR) and/or chemotherapy causes not only acute tissue damage but also late effects including long-term (or residual) bone marrow (BM) injury. The induction of residual BM injury is primarily attributable to the induction of hematopoietic stem cell (HSC) senescence. However, the molecular mechanisms by which IR and/or chemotherapy induces HSC senescence have not been clearly defined, nor has an effective treatment been developed to ameliorate the injury. Thus, we investigated these mechanisms in this study. The results from this study show that exposure of mice to a sublethal dose of total body irradiation (TBI) induced a persistent increase in reactive oxygen species (ROS) production in HSCs only. The induction of chronic oxidative stress in HSCs was associated with sustained increases in oxidative DNA damage, DNA double-strand breaks (DSBs), inhibition of HSC clonogenic function, and induction of HSC senescence but not apoptosis. Treatment of the irradiated mice with N-acetylcysteine after TBI significantly attenuated IR-induced inhibition of HSC clonogenic function and reduction of HSC long-term engraftment after transplantation. The induction of chronic oxidative stress in HSCs by TBI is probably attributable to the up-regulation of NADPH oxidase 4 (NOX4), because irradiated HSCs expressed an increased level of NOX4, and inhibition of NOX activity with diphenylene iodonium but not apocynin significantly reduced TBI-induced increases in ROS production, oxidative DNA damage, and DNA DSBs in HSCs and dramatically improved HSC clonogenic function. These findings provide the foremost direct evidence demonstrating that TBI selectively induces chronic oxidative stress in HSCs at least in part via up-regulation of NOX4, which leads to the induction of HSC senescence and residual BM injury.
KW - Free radicals
KW - Hematopoietic stem cells
KW - Ionizing radiation
KW - Oxidative stress
KW - Senescence
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U2 - 10.1016/j.freeradbiomed.2009.11.005
DO - 10.1016/j.freeradbiomed.2009.11.005
M3 - Article
C2 - 19925862
AN - SCOPUS:72649103214
SN - 0891-5849
VL - 48
SP - 348
EP - 356
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 2
ER -